Utilizing an LC/MS-MS-based feature-based molecular networking (FBMN) strategy, six undescribed PPAPs (1-6) characterized by an acetyl substituent at the C-1 position of their phloroglucinol scaffold, were efficiently isolated from the roots of Harrisonia perforata. Notably, compund 1 displays an unconventional 5/5/6/5 ring architecture, while compounds 5 and 6 represent the first case incorporating a benzofuran core and a geranyl-derived cyclohexanol unit. Their structures were unequivocally elucidated through comprehensive spectroscopic data analysis, TDDFT-ECD calculations, and X-ray crystallographic studies. Interestingly, compound 3 at 20 μM exhibited negligible cytotoxicity but significantly potentiated the activity of paclitaxel against HCT-15 cells by 42.8-fold. Mechanistic studies further demonstrated that compound 3 did not significantly alter the expression levels of ATP-binding cassette (ABC) transporters, but potently inhibited the transport function of both ABCB1 and ABCG2. Molecular docking reveals that compound 3 stably binds to the central substrate-binding cavities of ABCB1 and ABCG2, with its binding primarily stabilized by hydrogen bonds and hydrophobic interactions.

1,2,4-Triazole is a ubiquitous heterocycle of significance for pharmaceuticals, materials, and ligand design. A convergent, atom-economical strategy for the construction of this important moiety has been developed, leveraging functionalized heteroaryl hydrazonimides and carbaldehydes via iodine-mediated oxidative annulation in an efficient, scalable, and metal-free manner, providing completely chemoselective 1H- or 2H-3,5-disubstituted-1,2,4-triazoles of relevance to separation science and medicinal chemistry. The twenty-nine-example substrate scope is highlighted by rapid access to sp2- and sp3-hybridized substituents through carbaldehyde selection. Diversely functionalized pyridyl- and heteroaryl components were incorporated through a hydrazonimide synthon with several examples having relevance to unsymmetric, soft-N-donor complexant scaffolds utilized in minor actinide extraction in support of improving the sustainability of the nuclear fuel cycle. Single-crystal X-ray diffraction experiments confirmed the presence of 1H- and 2H-tautomers. Density functional theory computations provided support of a proposed mechanistic hypothesis. Method optimization, substrate scope, scale-up experiments, and a preliminary reaction mechanism are reported herein.

By modifying Dixon's ligands, cinchona-derived amide adamantylphosphine ligands were synthesized. When combined with silver salts, these ligands enabled highly efficient asymmetric aldol reactions using isocyanoacetates as eco-friendly C-N synthons. The catalytic system operated under mild conditions with accelerated kinetics, affording chiral oxazolines in up to 99% ee and >99:1 dr. Broad substrate scope was demonstrated with both aryl and alkyl aldehydes, and the method enabled atom-economical synthesis of key intermediates for thiamphenicol and chloramphenicol.

The Nozaki-Hiyama-Kishi (NHK) reaction serves as a powerful method for stereoselective carbon-carbon bond formation under mild conditions. While significant progress has been made in the enantioselective propargylation of carbonyl compounds, its application to imines remains underdeveloped. Herein, we report a catalytic asymmetric reductive propargylic addition to α-ketimino esters, providing direct access to chiral propargylated amines with high chemoselectivity and enantioselectivity. This method expands the synthetic utility of NHK-type reactions toward nitrogen-containing scaffolds, offering a complementary route to enantioenriched amine derivatives under mild and efficient conditions.

Reaction of rac-Tröger's base (TB) with aryl halides is described via ring opening with concomitant N-arylation in the presence of the t-BuOK/DMSO reagent system. The methylene bridge of the Tröger's base derivatives is eliminated by an aryne intermediate formed in situ, leading to the generation of N-arylated product in up to 67% yield. The reaction scope has also been extended to synthesize an enantiopure compound involving the rearrangement of the methylene bridge.

The electronic effects of Lewis acids (LAs) in nucleophilic substitution (SN) reactions are investigated from a molecular electron density theory (MEDT) perspective at the ωB97X-D/6-311G(d,p) level in dichloromethane. The LA-catalyzed ring-opening of two sulfonyl aziridines, typically classified as SN2-type processes, is analyzed, and the LA-assisted SN reactions of three N-alkylmethanesulfonamides toward the chloride anion. LAs do not significantly increase the electrophilicity ω of the substrate but markedly enhance the nucleofugality Λ of the sulfonamide-leaving group (LG), which governs SN feasibility. LAs lower activation enthalpies by over 17 kcal·mol-1, rendering the ring-opening of 2-phenylaziridines fully regioselective. Electron-density topological analyses show that at the transition-state structures (TSs), the C-N bond associated with the LG is already broken, whereas C-Cl bond formation has not begun, indicating a carbocation-like structure at the central carbon. A relative interacting atomic energy analysis of the LA-catalyzed ring-opening of 1-methanesulfonylaziridine by the chloride anion in the presence of Me4N+ reveals that stabilization of both the sulfonamide:LA LG and chloride accounts for the reduced activation barriers. LAs such as BF3 and AlCl3 enhance the LG ability (nucleofugality Λ) of sulfonamides, shifting the TS toward a more carbocation-like (SN1-like) structure and lowering the nucleophile participation.

Herein, we report efficient microwave-assisted one-pot protocols, enabling the efficient synthesis of a broad scope of functionalized pyrido[2,3-d]imidazoles. The developed methodologies allow obtaining target compounds using cheap reagents and catalysts, in very short reaction times, and perform three-step reactions in the same vessel without the need of intermediate isolation. The obtained pyridoimidazoles equipped with alkyl, alkoxy, hydroxy, halogen, acyl, and amino substituents were fully characterized and constitute useful materials for coordination chemistry or building blocks for further transformations.

Density functional theory (DFT) calculations were performed to elucidate the detailed mechanism of catalytic amide hydrogenation mediated by a Ru-PNNH complex bearing a tridentate ligand. Three key reactive sites were identified within the catalyst framework: the methylene group on the phosphine side arm (C1), the methylene group on the amine side arm (C4), and the amino group directly coordinated to the Ru center (N1). The catalytic cycle proceeds through three sequential stages: precatalyst activation, deamination, and aldehyde reduction. The deamination step in stage II, with a free energy barrier of 20.1 kcal/mol, is identified as the rate-determining step (RDS) of the overall catalysis. Among the three reactive sites, C4 shows the highest activity, serving as the key center for both the precatalyst activation and the aldehyde reduction stages. The Ru-coordinated amino group is crucial in the deamination stage, especially for C-N bond cleavage. Notably, a cooperative mechanism emerges during the deamination process, where C4 and N1 act in a complementary and alternating manner to drive the key steps. The synergistic interaction exemplifies metal-ligand cooperative catalysis, demonstrating how site-specific reactivity enhances the overall efficiency and selectivity of the transformation.

We report a highly enantioselective and efficient synthesis of C-3 substituted butenolides via a tandem C-H activation/Michael addition cascade, enabled by Rh/cinchonine dual catalysis. This strategy leverages the stability and accessibility of the achiral [Cp*RhCl2]2 complex in combination with the chiral induction provided by the naturally occurring alkaloid cinchonine, eliminating the need for complex chiral ligands. Importantly, this dual catalytic system represents the first enantioselective protocol that exploits simple acrylic acids as coupling partners, thereby extending the reactivity paradigm beyond conventional benzoic acid derivatives and significantly broadening the substrate scope beyond aromatic counterparts. The reaction proceeds in a one-pot fashion under mild conditions, delivering a wide range of products with good to very good enantiomeric excess.